Alzheimer's dementia (AD) is the most common form of cognitive impairment in older persons. AD is characterized pathologically by amyloid plaques and neurofibrillary tangles (NFT). Recent experiments provide a tenuous link between amyloid pathology and NFTs. However, NFTs can occur without concomitant amyloid pathology in a broad class of neurodegenerative diseases, collectively known as "tauopathies." This suggests that NFTs themselves are intricately involved in neurodegenerative processes. Despite the central role of neurofibrillary tangle formation to the pathogenesis of AD, little is known about the in vivo molecular events leading to the fibrillar aggregation of tau, the predominant protein component of NFTs. This proposal seeks to elucidate the critical molecular mechanisms leading to NFT formation, with the goal of identifying novel targets for therapeutic intervention to alleviate NFT formation in AD. In the proposed study we will confirm dysregulation of numerous novel genes associated with NFT pathology and use high-throughput functional validation assays to characterize the role of this gene dysregulation in the etiology of NFT formation and AD. Our preliminary results lead us to hypothesize that the CD47 signaling pathway contributes to abnormalities in tau metabolism. NFT formation, and neuronal cell death and dementia in AD. This hypothesis has been generated by stringent expression profiles of NFT and non-NFT neurons from AD patients and non-demented control individuals. We propose here to validate this pathway at the mRNA, protein, and functional levels, as well as to test the role of additional dysregulated genes in NFT pathogenesis. Information about the genes that are differentially expressed in neurons containing neurofibrillary tangles relative to histopathologically normal neurons from AD and unaffected individuals, combined with functional validation of those differences will greatly increase our understanding of the molecular mechanisms involved in the development of this dementia-inducing form of pathology. In addition, knowledge of the cellular signaling pathways that are affected during neurofibrillary tangle formation may provide novel targets for the discovery of interventions to treat and prevent tangle- induced dementia. Importantly, understanding the molecular basis for neurofibrillary tangle formation may be generally applicable to the treatment of other neurodegenerative tauopathies, such as progressive supranuclear palsy, Pick's disease, and corticobasal degeneration. Successful completion of this proposal will yield numerous novel targets for potentially efficacious therapeutic intervention in Alzheimer's disease. [unreadable] [unreadable]